Abstract Patients suffering from limb non-healing ulcers or gangrene caused by critical limb ischemia (CLI) induced by peripheral arterial occlusive disease (PAD) or diabetes are at very high risk of major amputation and experience poor physical function and severely diminished quality of life. Particularly, CLI in diabetic patients is associated with high rates of morbidity and mortality. CLI and diabetes-associated non-healing wound and gangrene result in over 130K major limb amputations and over $2 billion health care costs in the USA every year. There is a formidable need for novel therapeutic strategies. Our goal is to develop novel therapeutic strategies that will accelerate neovascularization and tissue repair to eliminate the need for major amputation. Cell- based therapy has emerged as a promising modality that can help to heal ulcers, increase ischemic limb functional recovery, prevent major amputation, and improve quality of life and survival in patients with CLI and diabetes. Bone marrow (BM)-derived tissue repair cells (TRC) represent an alternative beneficial therapeutic option to induce therapeutic angiogenesis and promote tissue regeneration. However, targeted systemic delivery of therapeutic cells to the disease tissues, which has certain advantages to local administration approach, remains one formidable challenge. We have recently developed a nanocarrier-mediated cell delivery method by coating the surface of the cells to be delivered with dendrimer nanocarriers modified with adhesion molecules. Nanocarriers can function as `GPS' to direct infused transplanting cells reach to destination via recognition and association with the counterpart adhesion molecules highly or selectively expressed on the activated endothelium in injured tissues. Once anchored on the activated endothelium, nanocarriers-coated cells extravasate and home to the targeted tissues to execute their therapeutic role. We thus propose to test and optimize this newly-developed targeted cell delivery platform to direct TRC specifically and efficiently home to ischemic and wound tissues to achieve therapeutic angiogenesis and tissue repair. Our proposal applies novel cell surface decoration method for targeted cell delivery, new mouse gangrene and powerful pig wound models to test feasibility and efficacy of novel nanocarrier-mediated targeted cell therapy in promoting tissue neovascularization and tissue repair. The proposed study is translatable for developing and optimizing safe and effective cell-based therapies for clinical trials. It may offer a new paradigm for advancing and transforming the field of non-invasive treatment for PAD/CLI.